The present invention relates to 2-substituted 4-heteroaryl-pyrimidines, their preparation, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders such as cancer, leukemia, psoriasis and the like.
Certain 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidineamines having anti-asthmatic properties are disclosed in EP-A-233,461. Certain 4-heteroaryl-N-(3-substituted-phenyl)-2-pyridineamines possessing anti-proliferative properties and inhibiting protein kinases C, epidermal growth factor receptor-associated tyrosine protein kinase (EGF-R-TPK), as well as CDK1/cyclin B have been disclosed in WO95/09847 wherein the exemplified heteroaryl are pyridyl and indolyl.
J. Med. Chem. (1993) Vol. 36, pages 2716-2725, Paul, R. et al: discloses a further class of phenyl amino-pyrimidines possessing anti-inflammatory activity. These compounds include mono-substituted 2-thienyl groups at the 4-position of the pyrimidine ring and dimethyl-3-furyl groups at this position.
It is an aim of the present invention to provide a further class of N-phenyl-2-pyrimidine anti-proliferative compounds. The compounds of the present invention have surprisingly been found to not to be inhibitors of protein kinase C. As discussed hereinafter, their activity may be demonstrated by inhibition of cell proliferation in cell lines and/or inhibition of cyclin dependent kinase enzymes. Throughout the specification, the term xe2x80x9cthienylxe2x80x9d is used interchangeably with xe2x80x9cthiophenexe2x80x9d.
The first aspect of the present invention relates to compounds of general formula I: 
wherein:
X1 is CH and X2 is S; or
one of X1 and X2 is S, and the other of X1 and X2 is N;
Z is NH, NHCO, NHSO2, NHCH2, CH2, CH2CH2, or CHxe2x95x90CH;
R1, R2, and R3 are independently H, alkyl, aryl, aralkyl, heterocycle, halogeno, NO2, CN, OH, alkoxy, aryloxy, NH2, NHxe2x80x94Rxe2x80x2, Nxe2x80x94(Rxe2x80x2)(Rxe2x80x3), NHxe2x80x94CORxe2x80x2, NH-aryl, N-(aryl)2, COOH, COOxe2x80x94Rxe2x80x2, COO-aryl, CONH2, CONHxe2x80x94Rxe2x80x2, CONxe2x80x94(Rxe2x80x2)(Rxe2x80x3), CONH-aryl, CON-(aryl)2, SO3H, SO2NH2, CF3, COxe2x80x94Rxe2x80x2, or CO-aryl, wherein alkyl, aryl, aralkyl, heterocycle and NH-aryl groups may be further substituted with one or more groups selected from halogeno, NO2, CN, OH, O-methyl, NH2, COOH, CONH2 and CF3; at least one of the groups R1 and R2 being other than H when either X1 or X2 is S;
R4, R5, R6, R7, and R8 are independently from each other H, substituted or unsubstituted lower alkyl, halogeno, NO2, CN, OH, substituted or unsubstituted alkoxy, NH2, NHxe2x80x94Rxe2x80x2, alkyl-aryl, alkyl-heteroaryl, NH(Cxe2x95x90NH)NH2, N(Rxe2x80x2)3+, Nxe2x80x94(Rxe2x80x2)(Rxe2x80x3), COOH, COOxe2x80x94Rxe2x80x2, CONH2, CONHxe2x80x94Rxe2x80x2, CONxe2x80x94(Rxe2x80x2)(Rxe2x80x3), SO3H, SO2NH2, CF3 or (CH2)nO(CH2)mNRxe2x80x2Rxe2x80x3, (CH2)nCO2(CH2)mORxe2x80x2xe2x80x3 wherein n is 0, 1, 2 or 3 and m is 1, 2 or 3;
wherein Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 are each independently alkyl groups that may be the same or different;
and pharmaceutically acceptable salts thereof.